Certain genotypes of human papillomavirus (HPV), designated 'high- risk', are the primary etiologic agents of cervical cancer. HPV16 is the prototypic high-risk genotype and present in half of all cervical cancers. Clinical trials of candidate HPV16 prophylactic vaccines underway at Johns Hopkins University offer a unique opportunity to identify immune correlates of clinical outcome. These vaccines comprise virus-like particles (VLPs) derived from HPV16L1 (with Alum or MF59 adjuvant or no adjuvant) and chimeric L1/L2-E2-E7 VLP. Passive transfer or immunoglobulin (IG) G of VLP-antiserum protects animals from experimental papillomavirus infection, indicating that humoral immunity effects protection. Our goal is to identify humoral parameters that best correlate with protection of patients and how they are influenced by vaccine administration. Specifically, we propose: Aim 1: Determine how the type of adjuvant and dose of antigen influences the antibody response of patients to HPV16 VLP vaccination. In addition to VLP-specific ELISA, we propose several novel immunoassays to further dissect the humoral response, including average avidity for HPV16 pseudovirion neutralization titer, hemagglutination inhibitor titer and post-binding HPV16 pseudovirion neutralization titer, hemagglutination inhibitor titer and post-binding HPV16 pseudovirion neutralization titer. Protection from HPV16 infection after parenteral vaccination is likely dependent upon serum IgG transduction to cervical secretion. Both serum and cervical secretions will be collected on the same visit from forty patients vaccinated with L1 VLPs and chimeric VLPs. To assess the relationship between antibody at these sites, we propose: Aim 2: Compare the properties of VLP-specific antibody of both serum and cervical secretion of vaccination patients. To examine the humoral mechanism that effects protection, we propose. Aim 3: Determine how serum antibody parameters in HPV16 VLP-vaccinated patients with breakthrough HPV16 infection compare with those of matched vaccines without detectible HPV infection. Because basal epithelia do not express L1 in vivo, the L1 VLP vaccine study is an important opportunity to determine the humoral contribution to protection against genital HPV. The importance of immune responses against early viral protein to protection against HPOV16 may be assessed by comparison of protective efficacy and both humoral and cell-mediated (Projects 2 & 3) immune responses generated by chimeric VLP (containing E2 and E7) and L1 only VLP. These studies will further rational development of vaccines against HPV and other sexually transmitted viruses.